Wolfgang Ch. Marsch

Superficial Inguinal and Radical Ilioinguinal Lymph Node Dissection in Patients with Palpable Melanoma Metastases to the Groin - An Analysis of Survival and Local Recurrence

The present study addresses the question whether an extended ilioinguinal dissection as compared to an only superficial inguinal dissection improves survival and/or local tumour control after the appearance of palpable melanoma metastases to the groin. We retrospectively analysed the data of 104 patients with 69 ilioinguinal and 35 superficial inguinal dissections (median follow up 127 months). Prognostic factors of survival and groin recurrence were assessed using Kaplan-Meier estimation and Cox proportional hazards model. By multifactorial analysis, metastatic involvement of two lymph nodes or less was associated with a significantly better survival rate than involvement of >2 or pelvic nodes (p=0.0002). After radical ilioinguinal dissection, patients with extremity-located primaries had a better prognosis than patients with truncal primaries (p=0.03). Tumour infiltration of the ilio-obturator compartment was found to be an independent factor of poor prognosis (p=0.0009). The probability of recurrence in the dissected groin paralleled the number of positive nodes and significantly increased if intransits were observed (p=0.0002). The extent of surgery, Breslow thickness, epidermal ulceration, sex, age and adjuvant chemotherapy neither significantly influenced survival nor local control rates. In summary, when metastatic inguinal nodes become palpable, the presence of pelvic metastases indicates systemic disease. After therapeutic groin dissection, local recurrence and survival depend rather on regional tumour burden than on the extent of surgery.The present study addresses the question whether an extended ilioinguinal dissection as compared to an only superficial inguinal dissection improves survival and/or local tumour control after the appearance of palpable melanoma metastases to the groin. We retrospectively analysed the data of 104 patients with 69 ilioinguinal and 35 superficial inguinal dissections (median follow up 127 months). Prognostic factors of survival and groin recurrence were assessed using Kaplan-Meier estimation and Cox proportional hazards model. By multifactorial analysis, metastatic involvement of two lymph nodes or less was associated with a significantly better survival rate than involvement of > 2 or pelvic nodes (p = 0.0002). After radical ilioinguinal dissection, patients with extremity-located primaries had a better prognosis than patients with truncal primaries (p = 0.03). Tumour infiltration of the ilio-obturator compartment was found to be an independent factor of poor prognosis (p = 0.0009). The probability of recurrence in the dissected groin paralleled the number of positive nodes and significantly increased if intransits were observed (p = 0.0002). The extent of surgery, Breslow thickness, epidermal ulceration, sex, age and adjuvant chemotherapy neither significantly influenced survival nor local control rates. In summary, when metastatic inguinal nodes become palpable, the presence of pelvic metastases indicates systemic disease. After therapeutic groin dissection, local recurrence and survival depend rather on regional tumour burden than on the extent of surgery.

Frequent occurrence of RASSF1A promoter hypermethylation and Merkel cell polyomavirus in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. It has recently been reported that integration of a Merkel cell polyomavirus (MCPyV) in receptor tyrosine phosphates type G (PTPRG) gene occurs in MCC, and that viral infections are associated with epigenetic silencing of tumor suppressor genes (TSG) in cancer. To examine whether a correlation between TSG inactivation and viral infection can be found in MCC, we investigated the promoter hypermethylation of RASSF1A, TP73, PTPRG, FHIT, and CDKN2A and the presence of MCPyV and SV40 in 98 MCC by PCR. Hypermethylation of RASSF1A was frequently found in 42 of 83 (51%) of MCC. Methylation of CDKN2A was present in 9 of 41 (22%) of MCC. Hypermethylation of TP73 (0%), PTPRG (4%), and FHIT (0%) was infrequent in MCC. Interestingly, MCPyV was found in 90 of 98 (92%) MCC, however, no SV40 signal was detected. No correlation between TSG hypermethylation and viral infection was found. Our results show frequent hypermethylation of RASSF1A and the presence of MCPyV in primary MCC, and that these events may contribute to the pathogenesis of MCC.

Hazard rates for recurrent and secondary cutaneous melanoma: An analysis of 33,384 patients in the German Central Malignant Melanoma Registry

BACKGROUND Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow-up examinations. OBJECTIVES This study aimed to analyze stage- and time-dependent hazard rates (HR) and discusses current surveillance recommendations. METHODS Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan-Meier estimates and HRs were calculated. RESULTS Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. LIMITATIONS As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. CONCLUSION For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account.

Hyperplasia of dermal microvascular pericytes in scleroderma

Background:  Pericytes (PCs) are smooth muscle‐like mural cells of capillaries and venules, which can synthesize matrix components and fibroblast‐activating cytokines, and are thus potential mediators of pathological changes in scleroderma. In this study, alterations in microvessels were quantitatively imaged, taking PC into account for the first time.

RASSF10 Promoter Hypermethylation Is Frequent in Malignant Melanoma of the Skin but Uncommon in Nevus Cell Nevi

The Ras association domain family (RASSF) consists of several tumor suppressor genes, which are frequently silenced in human cancers. We analyzed the epigenetic inactivation of RASSF2 and RASSF10 in malignant melanoma (MM) of the skin, including 5 MM cell lines, 28 primary MM, 33 metastases of MM, 47 nevus cell nevi (NCN), and 22 control tissues. The RASSF2 promoter was epigenetically downregulated in two MM cell lines only, but not in any of the investigated tumor samples. In contrast, hypermethylation of the RASSF10 promoter was found in all investigated cell lines, 19/28 (68%) of the primary MM and 30/33 (91%) of the MM metastases, 2/18 (11%) of the dysplastic NCN, and 0/29 (0%) of the non-dysplastic NCN (difference between MM and all nevi, P<0.001). RASSF10 promoter hypermethylation correlated with a reduced RASSF10 mRNA expression in 3/4 MM cell lines, and treatment with a DNA methylation inhibitor reactivated RASSF10 transcription. Furthermore, immunohistological RASSF10 expression corresponds negatively to its promoter methylation state. In summary, RASSF10 proved to be a characteristically epigenetically silenced tumor suppressor in melanomagenesis, and analysis of RASSF10 methylation status represents a new candidate tool to assist in discrimination between MM and NCN.

Human dermal pericytes express 3G5 ganglioside--a new approach for microvessel histology in the skin.

Background: Pericytes cover the abluminal surface of microvessels and play an important role in capillary regulation and pathology. Studies on pericytes have been hindered by the lack of specific markers with which to facilitate microscopic identification of this cell type. Expression of the cell surface 3G5 ganglioside antigen has been reported in cultured retinal and cardiac pericytes. The objective of this study was to determine the usefulness of monoclonal antibody 3G5 as a pericyte marker in human skin.

S1‐Leitlinie zur Therapie der Hidradenitis suppurativa/Acne inversa (ICD‐10 Ziffer: L73.2)

Christos C. Zouboulis, Falk G. Bechara, Klaus Fritz, Hjalmar Kurzen, Aikaterini I. Liakou, Wolfgang C. Marsch, Annett Milling, Alexander Nast, Maurizio Podda, Klaus M. Taube, Volker Wienert, Thomas Winkler (1) Klinik für Dermatologie, Venerologie und Allergologie/Immunologisches Zentrum, Städtisches Klinikum Dessau, Dessau (2) Klinik für Dermatologie, Venerologie und Allergologie, Ruhr-Universität Bochum, Bochum (3) Hautärzte und Laserzentrum Landau und Kandel, Landau (Pfalz)/Kandel; Universitätsklinik für Dermatologie, Inselspital Bern, Bern; Fachgebiet Dermatologie, Umweltmedizin und Gesundheitstheorie, Universität Osnabrück (4) Niedergelassener Dermatologe, Freising (5) Universitätsklinik und Poliklinik für Dermatologie und Venerologie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale) (6) Klinik für Dermatologie, Klinikum Frankfurt (Oder) GmbH, Frankfurt (Oder) (7) Abteilung für Evidenz-basierte Medizin, Klinik für Dermatologie, Venerologie und Allergologie, Charité-Universitätsmedizin Berlin, Berlin (8) Hautklinik, Klinikum Darmstadt (9) Früherer Leitlinie-Beauftragter, Aachen (10) Patientenvertreter, 1. Vorsitzender der Deutschen Interessengemeinschaft Akne inversa e.V., Ibbenbüren

N-methyl-D-aspartate receptors influence the intracellular calcium concentration of keratinocytes.

Abstract: In the present study, the distribution of ionotropic glutamate receptors of the N‐methyl‐D‐aspartate (NMDA)‐receptor type was immunohistochemically demonstrated in healthy human skin (n = 22) and healthy buccal mucosa (n = 20). Moreover, the intracellular calcium concentration of HaCaT‐cells and native human keratinocytes were studied under the influence of the selective agonist NMDA and the selective NMDA‐antagonist MK‐801.

Expression of epidermal N-methyl-D-aspartate receptors (NMDAR1) depends on formation of the granular layer--analysis in diseases with parakeratotic cornification.

Ionotrope glutamate receptors of the N-methyl-d-aspartate (NMDA) receptor type are expressed on keratinocytes and influence the intracellular calcium concentration. The importance of NMDA receptors in pathophysiological processes in the skin is, however, still unclear. Epidermal distribution patterns of NMDA receptors were investigated in dermatoses with parakeratotic cornification (psoriasis vulgaris and verrucae vulgares) and compared to the expression of filaggrin. The expression of NMDA receptors (R1 component) in paraffin-embedded normal epidermis (n=22), psoriasis vulgaris (n=21) and verrucae vulgares (n=23) was examined and evaluated by means of digital image analysis. For quantitative characterization of the distribution patterns, a quotient was formed of the expression in the stratum granulosum and stratum basale (“NMDA ratio”). The distribution of NMDAR1 was compared to the immunohistochemical expression of filaggrin. Additionally the expression of filaggrin was investigated in HaCaT cells after treatment with the NMDA receptor antagonist MK-801. NMDA receptors were demonstrated in the epidermis of all preparations. In healthy skin, the highest receptor density was found in the stratum granulosum. This distribution pattern was basically also present in the dermatoses examined. Thus, the occurrence of parakeratosis in psoriasis vulgaris, but not in verrucae vulgares, was characterized by a significant reduction in the NMDA ratio (reduced expression of NMDAR1 in the upper epidermis). The immunohistochemical distribution of filaggrin was similar to that of NMDAR1. In HaCaT cells MK-801 suppressed the expression of filaggrin. NMDA receptors are expressed in human epidermis under physiological conditions especially in the stratum granulosum. Their reduced expression within parakeratotic epidermis in psoriasis vulgaris may be evidence of impaired intracellular calcium influx in this disease.

Kongenitale melanozytäre Nävi

ZusammenfassungKongenitale melanozytäre Nävi sind gutartige, bei ca. 1–6% aller Menschen auftretende Tumoren der Haut. Sie bergen das Risiko einer Entartung zum malignen Melanom in sich, können mit einem Befall der weichen Hirnhäute vergesellschaftet sein (neurokutane Melanose) und stellen für die Betroffenen z. T. ein beachtliches kosmetisches und psychisches Problem dar. Das Entartungspotential kongenitaler Nävuszellnävi wird heute, im Gegensatz zu früheren Auffassungen, als relevant angesehen. Somit ist eine operative Entfernung grundsätzlich empfehlenswert. Große, nicht komplett exzidierbare Läsionen sollten schon in den ersten Lebenswochen durch Dermabrasion behandelt werden.SummaryCongenital melanocytic nevi are benign skin tumours with a population-based prevalence of 1–6%. They run an increased life-time risk of transformation into malignant melanoma. Additionally, they can be associated with an involvement of the leptomeninges (neurocutaneous melanosis), and may cause considerable cosmetic and psychic problems. In contrast to the past, the risk of congenital melanocytic nevi developing into melanoma is now regarded as well-established. Thus, excision is recommended whenever possible. Large lesions which do not allow complete excision should be treated by dermabrasion within the first weeks of life.